Gastrointestinal (Gl) hormones and cytokines regulate the health and function of the gut and contribute to the development of diseases of the gut, which are a major health care burden for the United States population. One of the main challenges in Gl endocrinology today is to delineate the interactions of Gl hormones and cytokines. To begin addressing this question, we have focused on transforming growth factor-beta (TGF-beta) receptors and their interactions with other Gl hormones. We chose TGF-beta because it is an important growth regulator of the normal Gl tract, and TGF-beta signaling pathway is altered during diseases of the gut, such as cancer. We have increasing evidence that the effects of TGF-beta are modulated, in part, by Gl hormones. Our preliminary data demonstrate that TGF-beta receptors and gastrin releasing peptide receptor (GRP-R) act in concert to induce gene expression, apoptosis and cell cycle arrest in intestinal epithelial cells. In human liver cells, we found that TGF-beta induces parathyroid hormone-related protein (PTHrP) expression and inhibits cell proliferation through a PTHrP-dependent mechanism. These results provide two different examples of interactions between TGF-beta and Gl hormones and support our novel central hypothesis that Gl hormones interact with TGF-beta to regulate gene expression and cellular responses in the Gl tract. To test this hypothesis, we will focus on two such interactions: the cooperation between TGF-beta receptors and GRPR in intestinal epithelial cells and the interaction of TGF-beta and PTHrP in liver cells. In Specific Aim 1, we will elucidate the molecular mechanisms of cooperation between TGF-beta receptors and GRP-R. We will determine whether p38MAPK or Smad3 is involved in TGF-beta receptors and GRP-R-induced gene expression, apoptosis and cell cycle arrest and whether TGF-beta receptors and GRP-R cross-talk leads to enhanced neoplastic transformation. We will also examine the expression patterns of TGF-beta signaling proteins, GRP-R and COX-2 in the diseased gut. In Specific Aim 2, we will elucidate the molecular mechanisms of interaction between TGF-beta and PTHrP. We will determine whether p38MAPK or Smad3 is involved in TGF-beta-induced PTHrP expression and whether PTHrP is involved in TGF-beta-induced apoptosis and cell cycle arrest. We will also examine the expression patterns of TGF-beta signaling proteins and PTHrP in the aging and diseased liver.